Collagen induced arthritis is an animal model for rheumatoid arthritis (RA)that shares a number of clinical, rheumatological, serological, and radiographic features with human disease. Type II collagen is a major component of articular hyalin cartilage and is a potential autoantigen in RA. Predisposition to RA is linked to MHC class II genes with haplotype HLA-DQ8/DR4showing the highest relative risk. We generated transgenic mice expressing human class II genes. The studies using these transgenic mice have resulted in a bonanza of very exciting new findings on arthritis. In the current proposal, we will describe a new HLA- linked mouse model which simulates many of the disease manifestations of human rheumatoid arthritis. We introduced our HLA class II genes into a "new" knockout mouse where all the endogenous class II genes were deleted (AEo). Surprisingly, HLA class II molecules are expressedon T cells in these mice, similar to human, and we have found that these class II molecules on T cells can present antigens. Preliminary studies using these new transgenic mice in collagen induced arthritis have shown the following parameters which are very similar to human rheumatoid arthritis. 1)The HLA-DR4transgenic mice show gender difference like human RA with highest susceptibility in female mice. 2) Both the DQ8 and DR4 transgenic mice produce rheumatoid factors similar to human RA. Using this new model, we will investigate 1) the role of HLA class II on T cells in the pathogenesis of the disease; 2) role of B cells, rheumatoid factors, and immune complexes in the disease process; 3) the mechanism which causes gender difference in arthritis, and the potential role of hormones; and 4) using HLA class II genes involved protection from arthritis, we will explore potential gene therapy for prevention and cure of disease in these mice. We will also generate new HLA class II transgenic mice expressing DRB4*0103 (OR53) to complete the human susceptible haplotype, and transgenic mice expressing DQ4 which is linked to RA in Asian populations to bring in the ethnic diversity in RA. These studies should reveal the mechanism by which human HLA class II genes predispose to human RA, and their role in the onset, severity, and modulation of the disease.